Grant Details
Grant Number: |
1R21CA252916-01A1 Interpret this number |
Primary Investigator: |
Zhou, Hang |
Organization: |
Yale University |
Project Title: |
Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk |
Fiscal Year: |
2021 |
Abstract
Project Summary/Abstract
Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk
Alcohol use and alcohol use disorder (AUD) are among the leading causes of death and disability worldwide.
Ethanol, i.e. beverage alcohol, is mainly oxidized by alcohol dehydrogenases (several ADH genes) to
acetaldehyde, which is then detoxified to acetate by aldehyde dehydrogenases (mainly ALDH2). Acetaldehyde
and alcoholic beverages are classified as carcinogenic to humans by the International Agency for Research on
Cancer. Cumulative epidemiological evidence has shown that alcohol consumption is associated with the
development of cancers including upper aerodigestive tract, breast, liver and colorectal cancer; 5.5% of all
cancers are attributable to alcohol, totaling 770,000 cases annually. A better understanding of the molecular
basis by which alcohol increases cancer risk could lead to improved treatment and preventative strategies.
Genome-wide association studies (GWASs) have identified risk genes for alcohol-related traits and cancers,
and some genes show pleiotropic effects on both. However, the genetic relationship between alcohol and
cancers remains largely unclear. Recently, large GWASs have been conducted on alcohol-related traits and
cancers, provided opportunities to answer the above question. The proposed study will take advantage of large
scale genetic data in multiple populations to discover genetic risk variants playing roles in both alcohol-related
traits (alcohol use and AUD) and alcohol-associated cancers, study the genetic correlations among them, and
investigate the genetic causality between alcohol traits and cancers using Mendelian Randomization (MR).
Additionally, by integrating summary data regarding large-scale gene expression, eQTL, mQTL, metabolomic
QTL and proteomic QTLs into 2-step MR, we aim to identify genes whose expression levels are associated
with alcohol-associated cancer variation, identify regulatory and epigenetic markers that mediate the
relationship between alcohol and cancers, and identify the relevant pathway mechanisms that involve
acetaldehyde and, potentially, other metabolites. This study will help us to understand better the genetic
mechanisms that underlie the relationship between alcohol traits and alcohol-associated cancers, with the
potential to improve disease prevention and treatment strategies.
Publications
Human genetics and epigenetics of alcohol use disorder.
Authors: Zhou H.
, Gelernter J.
.
Source: The Journal Of Clinical Investigation, 2024-08-15 00:00:00.0; 134(16), .
EPub date: 2024-08-15 00:00:00.0.
PMID: 39145449
Related Citations
Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits.
Authors: Galimberti M.
, Levey D.F.
, Deak J.D.
, Zhou H.
, Stein M.B.
, Gelernter J.
.
Source: Molecular Psychiatry, 2024-04-05 00:00:00.0; , .
EPub date: 2024-04-05 00:00:00.0.
PMID: 38580809
Related Citations
Neurogenetic underpinnings of nicotine use severity: Integrating the brain transcriptomes and GWAS variants via network approaches.
Authors: Yang B.Z.
, Xiang B.
, Wang T.
, Ma S.
, Li C.R.
.
Source: Psychiatry Research, 2024 Apr; 334, p. 115815.
EPub date: 2024-02-28 00:00:00.0.
PMID: 38422867
Related Citations
Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.
Authors: Zhou H.
, Kember R.L.
, Deak J.D.
, Xu H.
, Toikumo S.
, Yuan K.
, Lind P.A.
, Farajzadeh L.
, Wang L.
, Hatoum A.S.
, et al.
.
Source: Nature Medicine, 2023-12-07 00:00:00.0; , .
EPub date: 2023-12-07 00:00:00.0.
PMID: 38062264
Related Citations
Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program.
Authors: Cheng Y.
, Dao C.
, Zhou H.
, Li B.
, Kember R.L.
, Toikumo S.
, Zhao H.
, Gelernter J.
, Kranzler H.R.
, Justice A.C.
, et al.
.
Source: Translational Psychiatry, 2023-05-05 00:00:00.0; 13(1), p. 148.
EPub date: 2023-05-05 00:00:00.0.
PMID: 37147289
Related Citations
Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.
Authors: Zhou H.
, Kember R.L.
, Deak J.D.
, Xu H.
, Toikumo S.
, Yuan K.
, Lind P.A.
, Farajzadeh L.
, Wang L.
, Hatoum A.S.
, et al.
.
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-01-30 00:00:00.0; , .
EPub date: 2023-01-30 00:00:00.0.
PMID: 36747741
Related Citations
Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder.
Authors: Deak J.D.
, Levey D.F.
, Wendt F.R.
, Zhou H.
, Galimberti M.
, Kranzler H.R.
, Gaziano J.M.
, Stein M.B.
, Polimanti R.
, Gelernter J.
, et al.
.
Source: Jama Network Open, 2022-10-03 00:00:00.0; 5(10), p. e2238880.
EPub date: 2022-10-03 00:00:00.0.
PMID: 36301540
Related Citations
Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.
Authors: Topiwala A.
, Taschler B.
, Ebmeier K.P.
, Smith S.
, Zhou H.
, Levey D.F.
, Codd V.
, Samani N.J.
, Gelernter J.
, Nichols T.E.
, et al.
.
Source: Molecular Psychiatry, 2022 Oct; 27(10), p. 4001-4008.
EPub date: 2022-07-26 00:00:00.0.
PMID: 35879401
Related Citations
Alcohol Use and Use Disorder and Cancer Risk: Perspective on Causal Inference.
Authors: Zhou H.
, Vasiliou V.
.
Source: Complex Psychiatry, 2022 Sep; 8(1-2), p. 9-12.
EPub date: 2022-08-09 00:00:00.0.
PMID: 36601413
Related Citations
Associations between moderate alcohol consumption, brain iron, and cognition in UK Biobank participants: Observational and mendelian randomization analyses.
Authors: Topiwala A.
, Wang C.
, Ebmeier K.P.
, Burgess S.
, Bell S.
, Levey D.F.
, Zhou H.
, McCracken C.
, Roca-Fernández A.
, Petersen S.E.
, et al.
.
Source: Plos Medicine, 2022 Jul; 19(7), p. e1004039.
EPub date: 2022-07-14 00:00:00.0.
PMID: 35834561
Related Citations
Genome-wide meta-analysis of alcohol use disorder in East Asians.
Authors: Zhou H.
, Kalayasiri R.
, Sun Y.
, Nuñez Y.Z.
, Deng H.W.
, Chen X.D.
, Justice A.C.
, Kranzler H.R.
, Chang S.
, Lu L.
, et al.
.
Source: Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology, 2022-01-29 00:00:00.0; , .
EPub date: 2022-01-29 00:00:00.0.
PMID: 35094024
Related Citations